Solid dosage form comprising a fibrate

ABSTRACT

The invention provides stable, solid dosage forms and pharmaceutical compositions in particulate form comprising a fibrate, for example fenofibrate, dissolved in an non-aqueous vehicle in order to ensure improved bioavailability of the active ingredient upon oral administration relative to known fibrate formulations.

This application claims priority under 35 USC 119 (a)-(d) fromapplication no. Danish application no. PA 2003 01503, filed Oct. 10,2003, Danish Patent Application No. 2004 00464 filed Mar. 23, 2004, andDanish Patent Application No. 2004 01006, filed Jun. 25, 2004 and is anational phase application of PCT/DK04/000667, filed Oct. 1, 2004, thecontents each of which are incorporated herein by reference.

The present invention relates to novel solid dosage forms andpharmaceutical compositions comprising a fibrate, notably fenofibrate.Particularly, the invention discloses solid dosage forms havingincreased bioavailability. The solid dosage forms of the inventioncomprise fibrate dissolved in a suitable vehicle or mixture of vehicles.The dosage forms are especially intended for oral use and exhibitexcellent storage stability, i.e. are stable. The invention also relatesto methods for preparation of the solid dosage forms and pharmaceuticalcompositions and the use thereof.

BACKGROUND OF THE INVENTION

Fibrates are lipid regulating agents. Examples of fibrates includegemifibrozil, fenofibrate, bezafibrate, clofibrate and ciprofibrate. Thecompounds are regarded as prodrugs and are metabolised in vivo to theiractive metabolites. For illustrative purposes only, the following isbased on a specific example of a fibrate, namely fenofibrate.Fenofibrate is chemically named2-[4-(4-chlorobenzoyl]-2-methyl-propanoic acid, 1-methylethyl ester andhas the following structural formula:

Fenofibrate is a white solid. The compound is insoluble in water. Themelting point is 79-82° C. Fenofibrate is metabolised to the activesubstance fenofibric acid. Fenofibric acid has an elimination half-lifeof about 20 hours. Measurement of the detected amount of fenofibric acidin the blood of a patient can reflect the efficacy of fenofibrateuptake. Fenofibric acid produces reductions in total cholesterol(total-C), LDL-C, apo-lipoprotein B, total triglycerides, andtriglyceride rich lipoprotein (VLDL) in treated patients. In addition,treatment with fenofibrate results in increases in high densitylipoprotein (HDL) and apo-lipoprotein apoAI and apo AII. Fenofibrateacts as a potent lipid regulating agent offering unique and clinicaladvantages over existing products in the fibrate family of drugsubstances. Fenofibrate produces substantial reduction in plasmatriglyceride levels in hypertriglyceridemic patients and in plasmacholesterol and LDL-C in hypercholesterolemic and mixed dyslipidemicpatients.

Fenofibrate also reduces serum uric acid levels in hyperuricemic andnormal subjects by increasing the urinary excretion of uric acid.

Clinical studies have demonstrated that elevated levels of totalcholesterol, low density lipoprotein cholesterol (LDL-C), andapo-lipoprotein B (apo B) are associated with human atherosclerosis.Decreased levels of high density lipoprotein cholesterol (HDL-C) and itstransport complex, apolipoprotein A (apo AI and apo AII) are associatedwith the development of atherosclerosis.

Fenofibrate is also effective in the treatment of Diabetes Type II andmetabolic syndrome.

Fenofibrate is also indicated as adjunctive therapy to diet fortreatment of adult patients with hypertriglyceridemia (Fredrickson TypesIV and V hyperlipedemia). Improving glycemic control in diabeticpatients showing fasting chylomicronemia will usually reduce fastingtriglycerides and eliminate chylomicronemia and thereby obviating theneed for pharmacologic intervention.

Fibrates are drug substances known to be are poorly and variablyabsorbed after oral administration. Normally they are prescribed to betaken with food in order to increase the bioavailability.

There have been a number of improvements in dosage form of the currentlymost used fibrate, fenofibrate, in an effort to increase thebioavailability of the drug and hence it's efficacy. However, there isstill a need for improved dosage forms relative to the currentlyavailable compositions and dosage forms, which provide crystallinefenofibrate in micronized form. In particular, there remains a need fora composition and a dosage form exhibiting a suitable bioavailability,which substantially can reduce or overcome the differential between thebioavailability of the drug in patients who are fasted versus thebioavailability of the drug in patients who are fed, and/or whichsubstantially can reduce or overcome the intra- and/or inter-individualvariations observed with the current treatment with the availablecommercial products. Furthermore, there is also a need for novel dosageforms and/or compositions that enable reduction in observedside-effects.

Especially, there is an unmet need for developing a solid composition inparticulate form in which the fibrate is in a dissolved state and thatappears as a composition that is in the form of a powder, granules,granulates, particles, beads, pellets or other forms for particulatematerial and not in the form of a soft dosage form containing a liquidmedium.

SUMMARY OF THE INVENTION

The inventors have now found that the bioavailability of fenofibrate canbe significantly enhanced by dissolving a fibrate, for examplefenofibrate, in a suitable vehicle and using the resulting compositionfor preparing a solid dosage form, i.e. a dosage form excluding materialin liquid form. Fibrate, especially fenofibrate, is known to beinsoluble in water, but the present invention provides pharmaceuticalcompositions and formulations exhibiting immediate release profileswhich are contemplated having significantly increased in vivobioavailability in patients in need thereof. The advantages of a solidand stable dosage form useful for oral administration are well-known.

Accordingly, in a first aspect the present invention relates to a solidoral dosage form comprising a fibrate in a vehicle, which ishydrophobic, hydrophilic or water-miscible. Useful solid dosage formsare in the form of tablets, beads, capsules, grains, pills, granulates,granules, powder, pellets, sachets or troches, and useful fibrates are,fenofibrate, bezafibrate, clofibrate, ciprofibrate and activemetabolites and analogues thereof including any relevant fibric acidsuch as fenofibric acid.

In a second aspect, the invention relates to a pharmaceuticalcomposition comprising a fibrate in a vehicle, which is hydrophobic,hydrophilic or water-miscible; and in a further aspect, the inventionrelates to a solid pharmaceutical composition in particulate formcomprising a fibrate, a hydrophobic or a hydrophilic or water-misciblevehicle and an oil-sorption material, which composition exhibits an oilthreshold value of at least 10%.

In yet another aspect, the invention relates to a method ofmanufacturing the solid oral dosage form or the pharmaceuticalcomposition of the invention.

Further aspects of the invention are evident from the followingdescription. Comparison in vivo tests in dogs have shown, cf. theexamples herein, that solid dosage forms and compositions of theinvention exhibit significantly enhanced bioavailability of fenofibratecompared to commercially available solid dosage forms containing thesame active ingredient, i.e. to Tricor® tablet and Lipanthyl® capsules.

Further, it is strongly believed that the present invention providessolid dosage forms and/or compositions of fibrate capable ofsignificantly reducing the intra- and/or inter-individual variationnormally observed after oral administration. Furthermore, compositionsand/or dosage forms according to the invention provide for a significantreduced food effect, i.e. the absorption is relatively independent onwhether the patient takes the composition or dosage form together withor without any meal. It is contemplated that a modified release of thefibrate may reduce the number of gastro-intestinal related side effects.Furthermore, it is contemplated that a significantly larger amount ofthe fibrate is absorbed and, accordingly, an equally less amount isexcreted unchanged via feces.

DETAILED DESCRIPTION Definitions

As used herein, the term “active ingredient” or “active pharmaceuticalingredient” means any component that is intended to furnishpharmacological activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease, or to affect thestructure or any function of the body of man or other animals. The termincludes those components that may undergo chemical change in themanufacture of the drug product and are present in the drug product in amodified form intended to furnish the specified activity or effect.

In the present context, the term “hydrophilic” describes that something‘likes water’, i.e. a hydrophilic molecule or portion of a molecule isone that typically is electrically polarized and capable of forminghydrogen bonds with water molecules, enabling it dissolve more readilyin water than in oil or other “non-polar” solvents.

In the present context, the term “amphiphilic” describes a molecule (asa surfactant) having a polar water-soluble group attached to awater-insoluble hydrocarbon chain. Thus, one end of the molecule ishydrophilic (polar) and the other is hydrophobic (non-polar).

In the present context, the term “hydrophobic” denotes a compoundtending to be electrically neutral and non-polar, and thus preferringother neutral and nonpolar solvents or molecular environments.

As used herein, the term “water-miscible” denotes a compound being fullyor partly miscible with water. For example, certain polar lipids arepartly water-miscible.

As used herein, the term “vehicle” means any solvent or carrier in apharmaceutical product that has no pharmacological role. For example,water is the vehicle for xilocaine and propylene glycol is the vehiclefor many antibiotics.

In the present context, the term “solid dispersion” denotes a drug oractive ingredient or substance dispersed on a particulate level in aninert vehicle, carrier, diluent or matrix in the solid state, i.e.usually a fine particulate dispersion.

In the present context, the term “solid solution” denotes a drug oractive ingredient or substance dissolved on a molecular level in aninert vehicle, carrier, diluent or matrix in the solid state.

As used herein, the term “analogue” means a chemical compound that isstructurally similar to another.

The term “drug” means a compound intended for use in diagnosis, cure,mitigation, treatment, or prevention of disease in man or other animals.

In this context, the term “dosage form” a means the form in which thedrug is delivered to the patient. This could be parenteral, topical,tablet, oral (liquid or dissolved powder), suppository, inhalation,transdermal, etc.

As used herein, the term “bioavailability” denotes the degree means towhich a drug or other substance becomes available to the target tissueafter administration.

As used herein, the term “bioequivalency” denotes a scientific basis onwhich generic and brand name drugs are compared with one another. Forexample, drugs are bioequivalent if they enter circulation at the samerate when given in similar doses under similar conditions. Parametersoften used in bioequivalence studies are t_(max), c_(max),AUC_(0-infinity), AUC_(0-t). Other relevant parameters may be W₅₀, W₇₅and/or MRT. Accordingly, at least one of these parameters may be appliedwhen determining whether bioequivalence is present. Furthermore, in thepresent context, two compositions are regarded as bioequivalent if thevalue of the parameter used is within 80-125% of that of Prograf® or asimilar commercially available tacrolimus-containing product used in thetest.

In the present context “t_(max)” denotes the time to reach the maximalplasma concentration (c_(max)) after administration; AUC_(0-infinity) orAUC denotes the area under the plasma concentration versus time curvefrom time 0 to infinity; AUC_(0-t) denotes the area under the plasmaconcentration versus time curve from time 0 to time t; W₅₀ denotes thetime where the plasma concentration is 50% or more of C_(max); W₇₅denotes the time where the plasma concentration is 75% or more ofC_(max); and MRT denotes mean residence time for a fibrate such asfenofibrate (and/or an analogue thereof.

In this context, the term “medicine” means a compound used to treatdisease, injury or pain. Medicine is justly distributed into“prophylactic,” i.e. the art of preserving health, and “therapeutic”,i.e. the art of restoring health.

In the present context, the terms “controlled release” and “modifiedrelease” are intended to be equivalent terms covering any type ofrelease of tacrolimus from a composition of the invention that isappropriate to obtain a specific therapeutic or prophylactic responseafter administration to a subject. A person skilled in the art knows howcontrolled release/modified release differs from the release of plaintablets or capsules. The terms “release in a controlled manner” or“release in a modified manner” have the same meaning as stated above.The terms include slow release (that results in a lower C_(max) andlater t_(max), but t_(1/2) is unchanged), extended release (that resultsin a lower C_(max), later t_(max), but apparent t_(1/2) is longer);delayed release (that result in an unchanged C_(max), but lag time and,accordingly, t_(max) is delayed, and t_(1/2) is unchanged) as well aspulsatile release, burst release, sustained release, prolonged release,chrono-optimized release, fast release (to obtain an enhanced onset ofaction) etc. Included in the terms is also e.g. utilization of specificconditions within the body e.g. different enzymes or pH changes in orderto control the release of the drug substance.

In this context, the term “erosion” or “eroding” means a gradualbreakdown of the surface of a material or structure, for example of atablet or the coating of a tablet.

The Active Drug Substance

The drug or active substance of the dosage forms and pharmaceuticalcompositions of this invention is a fibrate. Examples of useful fibratesare bezafibrate, ciprofibrate, clinofibrate, clofibrate, etofylline,clofibrate, fenofibrate, gemfibrozil, pirifibrate, simfibrate andtocofibrate; particularly useful are gemfibrozil, fenofibrate,bezafibrate, clofibrate, ciprofibrate and active metabolites andanalogues thereof including any relevant fibric acid such as fenofibricacid. In a preferred embodiment, the fibrate is fenofibrate or ananalogue thereof. However, the dosage forms and compositions of theinvention may also comprise a mixture of two, three or even fourdifferent fibrates and/or fibric acids.

The concentration of fibrate in the vehicle is at least 10% w/w, basedon the total weight of the fibrate and the vehicle; preferably at least15% w/w, or at least 16% w/w, or at least 17% w/w, or at least 20% w/w,or at least 25% w/w, or at least 30% w/w, especially at least 35% w/w,based on the total weight of the fibrate and the vehicle; and theconcentration of fibrate in the vehicle is at the most 90% w/w, based onthe total weight of the fibrate and the vehicle, or at the most 80% w/w,or at the most 75% w/w, or at the most 70% w/w, or at the most 60% w/w,or at the most 50% w/w, or at the most 40% w/w, or not above 35% w/w,based on the total weight of the fibrate and the vehicle. Preferably,the fibrate is fully dissolved in the non-aqueous vehicle. However, aminor occurrence of crystalline or microcrystalline active drug may notinfluence on the enhanced bioavailability of the solid dosage forms andpharmaceutical compositions of the invention. Accordingly, at least 90%w/w of the fenofibrate is dissolved in the vehicle, preferably is atleast 93% w/w, or at least 95% w/w, or at least 97% w/w, or at least 98%w/w, or at least 99% w/w, or at least 99.5% w/w, or at least 99.9% w/w,of the fenofibrate present in the dosage form or the pharmaceuticalcomposition fully dissolved in the vehicle or the vehicle system.

In addition to the content of fibrate, the dosage forms andpharmaceutical compositions of the invention may comprise further activedrug substances, preferably one additional drug substances. Preferably,such an additional drug substance is of a type normally employed for thesame indications as fibrate. A specific example is ezetimibe. However,combination products with three or even four drug substances used forthe same indication are contemplated as well as combination productscomprising two, three or four active ingredients for differentindications or therapies.

Examples of additional drug substances are other antilipidemic agentslike statins; lipid regulators like: acipimox, binifibrate, etofibrate,niceritrol, nicofibrate, pirozadil, ronifibrate, tocoferil nicotinate;combination with cardiovascular drugs like ace inhibitors: alacepril,benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat,fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril,ramipril, spirapril, temocapril, teprotide, trandolapril, zofenopril;calcium channel blockers like: amlodipine, aranidipine, azelnidipine,barnidipine, benidipine, bepridil, cilnidipine, diltiazem, efonidipine,felodipine, gallopamil, isradipine, lacidipine, lercanidipine,manidipine, mibefradil, nicardipine, nifedipine, nilvadipine,nimodipine, nisoldipine, nitrendipine, verapamil; alpha-blockers like:alfuzosin, bunazosin, doxazosin, indoramin, naftopidil,phenoxybenzamine, phentolamine, prazosin, tamsulosin, terazosin,thymoxamine, tolazoline, urapidil; beta-blockers like: acebutolol,alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol,bevantolol, bisoprolol, bopindolol, bucindolol, bunitrolol, bupranolol,carazolol, carteolol, carvedilol, celiprolol, esmolol, indenolol,labetalol, landiolol, levobetaxolol, levobunolol, mepindolol,metipranolol, metoprolol, nadolol, nebivolol, nipradilol, oxprenolol,penbutolol, pindolol, propranolol, sotalol, talinolol, tertatolol,timolol; angiotensin ii blockers like: candesartan, eprosartan,irbesartan, losartan, olmesartan, tasosartan, ref. telmisartan,valsartan; vasodilators like: cadralazine, diazoxide, dihydralazine,endralazine, hydralazine, minoxidil, todralazine, tolazoline,carbocromen, cinepazet, ref. cloridarol, dilazep, etafenone, fendiline,hexobendine, oxyfedrine, trapidil, trimetazidine, azapetine, bamethan,bencyclane, buflomedil, butalamine, calcitonin gene-related peptide,cetiedil, cinepazide, cyclandelate, di-isopropylammonium ichloroacetate,fasudil, ifenprodil, inositol nicotinate, naftidrofuryl, nicotinylalcohol, oxpentifylline [pentoxifylline], pentifylline, pipratecol,propentofylline, raubasine, xantinol icotinat; centrally actinghypertensives: apraclonidine, brimonidine, clonidine, guanabenz,guanfacine, methyldopa, moxonidine, rilmenidine, tiamenidine; antiarrhythmic drugs like: ajmaline, cibenzoline, disopyramide,hydroquinidine, pirmenol, procainamide, quinidine, aprindine,mexiletine, tocainide, diprafenone, encainide, flecainide, lorcainide,pilsicainide, propafenone, bretylium, acecainide, amiodarone, azimilide,bretylium, cibenzoline, dofetilide, ibutilide, nifekalant, sotalol,cibenzoline, verapamil; anti platelets like: abciximab, aspirin,cilostazol, clopidogrel, cloricromen, dipyridamole, ditazole,eptifibatide, indobufen, lamffiban, orbofiban, picotamide, sarpogrelate,sibrafiban, ticlopidine, tirofiban, trapidil, triflusal, xemilofiban;diuretics like: acetazolamide, brinzolamide, diclofenamide, dorzolamide,methazolamide, azosemide, bumetanide, etacrynic acid, etozolin,frusemide, piretanide, torasemide, isosorbide, mannitol, amiloride,canrenone, potassium canrenoate, spironolactone, triamterene, altizide,bemetizide, bendrofluazide, benzthiazide, butizide, chlorothiazide,chlortalidone, clopamide, cyclopenthiazide, cycloithiazide, epitizide,hydrochlorothiazide, hydroflumethiazide, indapamide, mebutizide,mefruside, methyclothiazide, meticrane, metolazone, polythiazide,quinethazone, teclothiazide, trichlormethiazide, tripamide, xipamide;antidiabetic drugs like: acarbose acetohexamide biguanide antidiabetcsbuformin carbutamide chlorpropamide epalrestat glibenclamide glibomuridegliclazide glimepiride glipizide gliquidone glisentide glisolamideglisoxepide glybuzole glyclopyramide glycyclamide glymidine sodiummefformin hydrochloride midaglizole miglitol nateglinide phenforminhydrochloride pimagedine pioglitazone hydrochloride pramlintiderepaglinide rosiglitazone sorbinil tolazamide tolbutamide troglitazonevoglibose substances like: q10, vitamins (nicotinamid, pyridoxine hcl,b12, tocopheroles, ascorbic acids, and others), and antioxidants ingeneral are also included in the useful combinations.

The additional drug substance or substances may also be included in orused in combination with drugs that may lead to an undesired level oftriglycerides and/or cholesterol. Thus, a composition according to theinvention may be included in or used in combination with drugs like e.g.isotretinoin or a retroviral protease inhibitor like HIV proteaseinhibitors, with an antipsychotic like olanzapine and others.

As mentioned, combination products with fibrates are not limited tocombinations of two active substances, triple or quadruple therapiescould also be of particular interest.

The Vehicle

Vehicles useful in the present context are vehicles, which arewater-miscible, hydrophilic or hydrophobic. Useful vehicles arenon-aqueous substances.

Examples of hydrophobic vehicles useful in the present invention arestraight chain saturated hydrocarbons, paraffins; fats and oils such ascacao butter, beef tallow, lard; higher fatty acid such as stearic acid,myristic acid, palmitic acid; hydrogenated tallow, substituted and/orunsubstituted triglycerides, yellow beeswax, white beeswax, carnaubawax, castor wax, japan wax, and mixtures thereof.

Examples of water-miscible vehicles useful in the present invention arewater-miscible polar lipids such as sorbitan esters, polyether glycolesters; higher alcohols such as cetanol, stearyl alcohol; glycerylmonooleate, substituted and/or unsubstituted monoglycerides, substitutedand/or unsubstituted diglycerides, and mixtures thereof. In a morepreferred embodiment, the vehicle is hydrophilic or water-miscible.Preferably, the vehicle is selected from the group consisting ofpolyethylene glycols, polyoxyethylene oxides, poloxamers,polyoxyethylene stearates, poly-epsilon caprolactone and mixturesthereof. However, the vehicle may advantageously also be apolyglycolized glyceride such as one of the numerous products sold underthe registered trade mark Gelucire®, for example Gelucire 44/14.

Examples of useful hydrophilic or water-miscible vehicles arepolyvinylpyrrolidones, polyvinylpolyvinylacetate copolymers (PVP-PVA),polyvinyl alcohol (PVA), PVP polymers, acrylic polymers, polymethacrylicpolymers (Eudragit RS; Eudragit RL, Eudragit NE, Eudragit E), myristylalcohol, cellulose derivatives including hydroxypropyl methyl-cellulose(HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodiumcarboxymethylcellulose, hydroxyethyl cellulose, pectins, cyclodextrins,galactomannans, alginates, carragenates, xanthan gums and mixturesthereof.

The vehicle is preferably a mixture of two or more substances.

The vehicle may also be an oily material as defined and described below.

Preferably, the melting point of the vehicle is preferably in the rangeof 10° C. to 250° C., preferably in the range of 30° C. to 100° C., morepreferably in the range of 40° C. to 75° C., especially in the range of40° C. to 70° C.

In a preferred embodiment of the invention, the vehicle is polyethyleneglycol (PEG), preferably having an average molecular weight of at least3000, more preferably at least 4000, optionally in admixture with apoloxamer such as e.g. poloxamer 188, in a preferred weight ratio ofbetween 1:3 and 10:1, preferably between 1:1 and 5:1, more preferablybetween and 3:2 4:1, especially between 2:1 and 3:1, in particular about7:3.

Bioavailability

In general, it is known that the absorption and bioavailability of atherapeutically active substance can be affected by a variety of factorswhen administered orally. Such factors include the presence of food inthe gastrointestinal tract and, in general, the gastric residence timeof a drug substance is significantly longer in the presence of food thanin the fasted state. If the bioavailability of a drug substance isaffected beyond a certain point due to the presence of food in thegastrointestinal tract, the drug substance is said to exhibit a foodeffect. Food effects are important because there is a risk associatedwith administering the drug substance to a patient who has eatenrecently. The risk derives from the potential that absorption into thebloodstream may be adversely affected to the point that the patientrisks insufficient absorption to remedy the condition for which the drugwas administered. In the case of e.g. fenofibrate the situation isdifferent in that food increases the uptake. Thus, lack of intake offood simultaneously with the drug substances may lead to insufficientabsorption. The extent of absorption of a commercially available productTricor® containing fenofibrate (from Abbott) is increased byapproximately 35% under fed as compared to fasting conditions.

As described above, there remains a need for new pharmaceuticalcompositions comprising one or more fibrates exhibiting, suitablebioavailability of the active compound and/or reduced or eliminated foodeffect. In the present context, the term “suitable bioavailability” isintended to mean that administration of a composition according to theinvention will result in a bioavailability that is improved compared tothe bioavailability obtained after administration of the activesubstance(s) in a plain tablet; or the bioavailability is at least thesame or improved compared to the bioavailability obtained afteradministration of a commercially available product containing the sameactive substance(s) in the same amounts. In particular it is desired toobtain more complete uptake of the active compound, and thereby providefor a possible reduction of the administered dosages. Further,pharmaceutical compositions and dosage forms comprising a fibrate mayalso reduce or negate the need for food to be takes simultaneously withthe dosage form thereby allowing patients more freedom on when the drugis taken. Also, improved or enhanced bioavailability will lead to animproved treatment because it will be possible to obtain the sametherapeutic response with a decreased dose and/or a less frequentadministration and less variability in plasma levels and no foodrestrictions. Another way of obtaining an improved treatment ofconditions where e.g. fenofibrate is indicated is by balancing therelease of fenofibrate to the gastro-intestinal tract in such a mannerthat an enhanced plasma concentration of fenofibrate is obtainedinitially or delayed with respect to the time of administration, i.e. byapplying modified or delayed release compositions containing one or morefibrates.

In one embodiment, the invention relates to a pharmaceutical compositionin particulate form or solid dosage form comprising one or morefibrates, wherein the composition upon oral administration to a mammalin need thereof exhibits an AUC/AUC_(Control) value of at least about1.0, the AUC_(Control) being determined using a commercially availableproduct containing the same fibrate, and the AUC values being determinedunder similar conditions.

No absolute bioavailability data based on an injectable composition areavailable e.g. for fenofibrate (most likely due to solubility problemsin aqueous media). The commercially available compositions containingfenofibrate include surface-active agents and/or e.g. a lipophilicmedium. The surface-active agents may impart improved bioavailabilityand therefore, the bioavailability of such a composition may besufficient already. However, there is still a need for developing aflexible formulation technique that enables preparation of a variety ofdosage forms. Accordingly, the requirement to such improved and/or moreflexible compositions may be to obtain the same or betterbioavailability than already seen from the commercially availableproducts.

Accordingly, in further embodiments of the invention, theAUC/AUC_(Control) value obtained by administering the solid dosage formor pharmaceutical composition of the invention is at least about 1.1such as, e.g., at least about 1.2, at least about 1.3, at least about1.4, at least about 1.5, about 1.75 or more, about 1.8 or more, about1.9 or more, about 2.0 or more, about 2.5 or more, about 2.75 or more,about 3.0 or more, about 3.25 or more, about 3.5 or more, about 3.75 ormore, about 4.0 or more, about 4.25 or more, about 4.5 or more, about4.75 or more or about 5.0 or more, the AUC values being determined undersimilar conditions.

Likewise, the c_(max) value obtained by administering the solid dosageform or pharmaceutical composition of the invention relative to thec_(max) value of commercially available Tricor® tablets is at leastabout 1.1, or at least about 1.2, or at least about 1.3, or at leastabout 1.4, or at least about 1.5, or at least about 1.6 or more, or atleast about 2.0, or at least about 2.5, or at least about 3.0, thec_(max) values being determined under similar conditions.

Another object of the invention is to reduce or eliminate the foodeffect. Thus, in another aspect, the invention relates to apharmaceutical composition in particulate form or solid dosage formcomprising one or more fibrates, wherein the composition or solid dosageform upon oral administration to a mammal in need thereof does notexhibit a significant adverse food effect as evidenced by a value of(AUC_(fed)/AUC_(fasted)) of at least about 0.85 with a lower 90%confidence limit of at least 0.75. In a specific embodiment, thepharmaceutical composition or solid dosage form of the invention has avalue of (AUC_(fed)/AUC_(fasted)) that is about 0.9 or more such as,e.g., about 0.95 or more, about 0.97 or more or about 1 or more.

In other words, the difference between a bioequivalence parametermeasured after oral administration to a mammal with and without food,respectively, is less than 25% such as, e.g., less than 20%, less than15%, less than 10% or less than 5%.

In another aspect, the invention relates to a pharmaceutical compositionin particulate form or solid dosage form comprising a fibrate, whereinthe composition upon oral administration to a mammal in need thereof isessentially bioequivalent with a commercially available productcontaining the same fibrate when administered in the same or lower doseas the commercially available product containing the same fibrate. Inspecific embodiments thereof, the dose is at the most about 98% w/w suchas, e.g., at the most about 95% w/w, at the most about 90% w/w, at themost about 85% w/w, at the most about 80% w/w, at the most about 75%w/w, at the most about 70% w/w, at the most about 65% w/w, at the mostabout 60% w/w, at the most about 55% w/w or at the most about 50% w/w ofthe dose of the fibrate administered in the form of a commerciallyavailable product containing the same fibrate.

Normally, the bioequivalence is determined by means of at least one ofthe following parameters: t_(max) (time to reach maximal plasmaconcentration), c_(max) (maximal plasma concentration), AUC_(0-t) (areaunder the curve from time 0 to time t), AUC_(0-infinity) (area under thecurve from time 0 to time infinity), W₅₀ (time period where the plasmaconcentration is 50% or more of c_(max)), W₇₅ ((time period where theplasma concentration is 75% or more of c_(max)) and/or MRT (meanresidence time).

A major problem with treatment with a fibrate is the large intra- orinter-individual variation. Thus, in a further aspect the inventionrelates to a pharmaceutical composition in particulate form comprisingone or more fibrates, wherein the composition upon oral administrationto a mammal in need thereof reduces inter- and/or intra-individualvariations compared to those of a commercially available productcontaining the same fibrate under the same conditions and in a dose thatprovides an equivalent therapeutic effect.

In the comparison tests mentioned above, the commercially availableproduct is Tricor® in the form of tablets or, alternatively, Tricor® inthe form of capsules, when the fibrate is fenofibrate. When the fibrateis gemfibrozil then a suitable commercially available product is Lopid®;when the fibrate is bezafibrate a suitable commercially availableproduct is Bezalip®; when the fibrate is clofibrate then a suitablecommercially available product is Atromid®; and when the fibrate isciprofibrate then a suitable commercially available product is Lipanon®.

A convenient method for determining whether a suitable amount of afibrate has been absorbed may be to determine the content of unchangedfibrate excreted via the feces. Thus, in one embodiment the inventionrelates to a solid pharmaceutical composition or solid dosage form,wherein at most about 25% w/w such as, e.g., at the most about 20% w/w,at the most about 15% w/w, at the most about 10% w/w, at the most about5% w/w of the fibrate contained in the composition is excreted in thefeces after oral administration.

Method of Manufacture

The particulate composition of the invention may be prepared by anymethod which is suitable for incorporation of poorly water-solubleactive substances. The pharmaceutical compositions may be prepared byany convenient method such as, e.g. granulation, mixing, spray dryingetc. A particularly useful method is the method disclosed in theinternational application published as WO 03/004001, which describes aprocess for preparation of particulate material by a controlledagglomeration method, i.e. a method, which enables a controlled growthin particle size. The method involves spraying a first compositioncomprising the active substance and a vehicle in liquid form onto asolid carrier. Normally, the vehicle has a melting point of at least 5°C., but the melting point must indeed be below the melting point of theactive substance. In the present invention, the melting point of thevehicle and should not exceed 250° C.

It is within the skills of the average practitioner to select a suitablevehicle being pharmaceutical acceptable, capable of dispersing or fullyor at least partly dissolving the active substance and having a meltingpoint in the desired range using general knowledge and routineexperimentation. Suitable candidate for carriers are described in WO03/004001, which is herein incorporated by reference.

In the present context, suitable vehicles are e.g. those mentioned asvehicles or as oily materials as well as those disclosed in WO03/004001. An advantage of using the controlled agglomeration methoddescribed in WO 03/004001 is that it is possible to apply a relativelylarge amount of a liquid system to a particulate material without havingan undesirable growth in particle size. Accordingly, in one embodimentof the invention, the particulate material of a pharmaceuticalcomposition has a geometric weight mean diameter d_(gw) of ≧10 μm suchas, e.g. ≧20 μm, from about 20 to about 2000, from about 30 to about2000, from about 50 to about 2000, from about 60 to about 2000, fromabout 75 to about 2000 such as, e.g. from about 100 to about 1500 μm,from about 100 to about 1000 μm or from about 100 to about 700 μm, or atthe most about 400 μm or at the most 300 μm such as, e.g., from about 50to about 400 μm such as, e.g., from about 50 to about 350 μm, from about50 to about 300 μm, from about 50 to about 250 μm or from about 100 toabout 300 μm.

The compositions and dosage forms of the invention are preferably formedby spray drying techniques, controlled agglomeration, freeze-drying orcoating on carrier particles or any other solvent removal process. Thedried product contains the active substance present preferably indissolved form either fully dissolved as a solid solution or partlydissolved as a solid dispersion including a molecular dispersion and asolid solution.

However, the composition and dosage forms of the invention arepreferably manufactured by a method comprising the steps of:

i) bringing the vehicle in liquid form, i.e. melting the vehicle ifsolid at room temperature,

ii) maintaining the liquid vehicle at a temperature below the meltingpoint of the fibrate,

iii) dissolving the desired amount of fibrate in the vehicle,

iv) spraying the resulting solution onto a solid carrier having atemperature below the melting point of the vehicle,

v) mechanically working the resulting composition to obtain particles,i.e. a particulate material, and

vi) optionally subjecting the particulate material to conventionalmethods for preparing solid dosage forms.

The pharmaceutical compositions comprising the active substance at leastpartly in form of a solid dispersion or solution may in principle beprepared using any suitable procedure for preparing pharmaceuticalcompositions known within the art. A solid dispersion may be obtained indifferent ways e.g. by employing organic solvents or by dispersing ordissolving the active substance in another suitable medium (e.g. an oilymaterial that is in liquid form at room temperature or at elevatedtemperatures). Solid dispersions (solvent method) are prepared bydissolving a physical mixture of the active substance (e.g. a drugsubstance) and the carrier in a common organic solvent, followed byevaporation of the solvent. The carrier is often a hydrophilic polymer.Suitable organic solvents include pharmaceutical acceptable solvent inwhich the active substance is soluble such as methanol, ethanol,methylene chloride, chloroform, ethylacetate, acetone or mixturesthereof.

Suitable water-soluble carriers include polymers such as polyethyleneglycol, poloxamers, polyoxyethylene stearates,poly-epsilon-caprolactone, polyvinylpyrrolidone (PVP),polyvinylpyrrolidone-polyvinylacetate copolymer PVP-PVA (Kollidon VA64),polymethacrylic polymers (Eudragit RS, Eudragit RL, Eudragit NE,Eudragit E) and polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), methyl cellulose, andpoly(ethylene oxide) (PEO).

Polymers containing acidic functional groups may be suitable for soliddispersions, which release the active substance in a preferred pH rangeproviding acceptable absorption in the intestines. Such polymers may beone ore more selected from the group comprising hydroxypropylmethylcellulose phtalate (HMPCP), polyvinyl acetate phtalate (PVAP),hydroxypropylmethylcellulose acetate succinate (HPMCAS), alginate,carbomer, carboxymethylcellulose, methacrylic acid copolymer (EudragitL, Eudragit S), shellac, cellulose acetate phthalate (CAP), starchglycolate, polacrylin, methyl cellulose acetate phtalate,hydroxypropyulcellulose acetate phthalate, cellulose acetateterephtahalate, cellulose acetate isophthalate and cellulose acetatetrimellitate.

The weight ratio of active substance to polymer may be in a range offrom about 3:1 to about 1:20. However, narrower ranges of from about 3:1to about 1:5, such as, e.g., from about 1:1 to about 1:3 or about mayalso be used.

Apart from using the organic solvent based method, solid dispersion orsolid solutions of one or more fibrates may be also obtained bydispersing and/or dissolving the active compound in the carriercomposition used in the controlled agglomeration method. Stabilizingagents etc. may be added in order to ensure the stability of the soliddispersion/solution.

Pharmaceutical Excipients and Additives

In the present context the terms “pharmaceutically acceptable excipient”are intended to denote any material, which is inert in the sense that itsubstantially does not have any therapeutic and/or prophylactic effectper se. Such excipient(s) may be added with the purpose of making itpossible to obtain a pharmaceutical, cosmetic and/or foodstuffcomposition, which have acceptable technical properties.

Examples of suitable excipients for use in a composition or solid dosageform according to the invention include fillers, diluents, glidants,disintegrants, binders, lubricants etc. or mixture thereof. As thecomposition or solid dosage form according to the invention may be usedfor different purposes, the choice of excipients is normally made takensuch different uses into considerations. Other pharmaceuticallyacceptable excipients for suitable use are e.g. acidifying agents,alkalizing agents, preservatives, antioxidants, buffering agents,chelating agents, coloring agents, complexing agents, emulsifying and/orsolubilizing agents, flavors and perfumes, humectants, sweeteningagents, wetting agents etc.

Examples of suitable fillers, diluents and/or binders include lactose(e.g. spray-dried lactose, α-lactose, β-lactose, Tabletose®, variousgrades of Pharmatose®, Microtose® or Fast-Floc®), microcrystallinecellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® orSolka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (lowsubstituted), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E, Fand K, Metolose SH of Shin-Etsu, Ltd, such as, e.g. the 4,000 cps gradesof Methocel E and Metolose 60 SH, the 4,000 cps grades of Methocel F andMetolose 65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K;and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH),methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C,Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodiumcarboxymethylcellulose, carboxymethylene,carboxymethylhydroxyethylcellulose and other cellulose derivatives,sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starchesor modified starches (including potato starch, maize starch and ricestarch), calcium phosphate (e.g. basic calcium phosphate, calciumhydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate,calcium carbonate, sodium alginate, collagen etc.

Specific examples of diluents are e.g. calcium carbonate, dibasiccalcium phosphate, tribasic calcium phosphate, calcium sulfate,microcrystalline cellulose, powdered cellulose, dextrans, dextrin,dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch,pregelatinized starch, sucrose, sugar etc.

Specific examples of disintegrants are e.g. alginic acid or alginates,microcrystalline cellulose, hydroxypropyl cellulose and other cellulosederivatives, croscarmellose sodium, crospovidone, polacrillin potassium,sodium starch glycolate, starch, pregelatinized starch, carboxymethylstarch (e.g. Primogel® and Explotabo®) etc. Specific examples of bindersare e.g. acacia, alginic acid, agar, calcium carrageenan, sodiumcarboxymethylcellulose, microcrystalline cellulose, dextrin,ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropylmethylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinizedstarch etc.

Glidants and lubricants may also be included in the second composition.Examples include stearic acid, magnesium stearate, calcium stearate orother metallic stearate, talc, waxes and glycerides, light mineral oil,PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils,corn starch, sodium stearyl fumarate, polyethylene glycols, alkylsulfates, sodium benzoate, sodium acetate etc.

Other excipients which may be included in a composition or solid dosageform of the invention are e.g. flavoring agents, coloring agents,taste-masking agents, pH-adjusting agents, buffering agents,preservatives, stabilizing agents, anti-oxidants, wetting agents,humidity-adjusting agents, surface-active agents, suspending agents,absorption enhancing agents, agents for modified release etc.

Other additives in a composition or a solid dosage form according to theinvention may be antioxidants like e.g. ascorbic acid, ascorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorous acid, monothioglycerol, potassium metabisulfite, propylgallate, sodium formaldehylde sulfoxylate, sodium metabisulfite, sodiumthiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherolhemisuccinate, TPGS or other tocopherol derivatives, etc. The carriercomposition may also contain e.g. stabilising agents. The concentrationof an antioxidant and/or a stabilizing agent in the carrier compositionis normally from about 0.1% w/w to about 5% w/w.

A composition or solid dosage form according to the invention may alsoinclude one or more surfactants or substances having surface-activeproperties. It is contemplated that such substances are involved in thewetting of the slightly soluble active substance and thus, contributesto improved solubility characteristics of the active substance. Suitablesurfactans for use in a composition or a solid dosage form according tothe invention are surfactants such as, e.g., hydrophobic and/orhydrophilic surfactants such as those disclosed in WO 00/50007 in thename of Lipocine, Inc.

Specific examples of suitable surfactants are polyethoxylated fattyacids such as, e.g. fatty acid mono- or diesters of polyethylene glycolor mixtures thereof such as, e.g. mono—or diesters of polyethyleneglycol with lauric acid, oleic acid, stearic acid, myristic acid,ricinoleic acid, and the polyethylene glycol may be selected from PEG 4,PEG 5, PEG 6, PEG 7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG 20, PEG25, PEG 30, PEG 32, PEG 40, PEG 45, PEG 50, PEG 55, PEG 100, PEG 200,PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG5000, PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG 1000, PEG 10,000, PEG15,000, PEG 20,000, PEG 35,000, polyethylene glycol glycerol fatty acidesters, i.e. esters like the above-mentioned but in the form of glycerylesters of the individual fatty acids; glycerol, propylene glycol,ethylene glycol, PEG or sorbitol esters with e.g. vegetable oils likee.g. hydrogenated castor oil, almond oil, palm kernel oil, castor oil,apricot kernel oil, olive oil, peanut oil, hydrogenated palm kernel oiland the like, polyglycerized fatty acids like e.g. polyglycerolstearate, polyglycerol oleate, polyglycerol ricinoleate, polyglycerollinoleate, propylene glycol fatty acid esters such as, e.g. propyleneglycol monolaurate, propylene glycol ricinoleate and the like, mono- anddiglycerides like e.g. glyceryl monooleate, glyceryl dioleae, glycerylmono- and/or dioleate, glyceryl caprylate, glyceryl caprate etc.; steroland sterol derivatives; polyethylene glycol sorbitan fatty acid esters(PEG-sorbitan fatty acid esters) such as esters of PEG with the variousmolecular weights indicated above, and the various Tween® series;polyethylene glycol alkyl ethers such as, e.g. PEG oleyl ether and PEGlauryl ether; sugar esters like e.g. sucrose monopalmitate and sucrosemonolaurate; polyethylene glycol alkyl phenols like e.g. the Triton® Xor N series; polyoxyethylene-polyoxypropylene block copolymers such as,e.g., the Pluronic® series, the Synperonic® series, Emkalyx®, Lutrol®,Supronic® etc. The generic term for these polymers is “poloxamers” andrelevant examples in the present context are Poloxamer 105, 108, 122,123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235,237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403 and 407;sorbitan fatty acid esters like the Span® series or Ariacel® series suchas, e.g. sorbinan monolaurate, sorbitan monopalmitate, sorbitanmonooleate, sorbitan monostearate etc.; lower alcohol fatty acid esterslike e.g. oleate, isopropyl myristate, isopropyl palmitate etc.; ionicsurfactants including cationic, anionic and zwitterionic surfactantssuch as, e.g. fatty acid salts, bile salts, phospholipids, phosphoricacid esters, carboxylates, sulfates and sulfonates etc.

When a surfactant or a mixture of surfactants is present in acomposition or a solid dosage form of the invention, the concentrationof the surfactant(s) is normally in a range of from about 0.1-80% w/wsuch as, e.g., from about 0.1 to about 20% w/w, from about 0.1 to about15% w/w, from about 0.5 to about 10% w/w, or alternatively, from about0.10 to about 80% w/w such as, e.g. from about 10 to about 70% w/w, fromabout 20 to about 60% w/w or from about 30 to about 50% w/w.

In a specific aspect of the invention, the at least one of the one ormore pharmaceutically acceptable excipients is selected from the groupconsisting of silica acid or a derivative or salt thereof includingsilicates, silicon dioxide and polymers thereof; magnesiumaluminosilicate and/or magnesium aluminometasilicate, bentonite, kaolin,magnesium trisilicate, montmorillonite and/or saponite, Nuesellin™.

Sorption Materials

Materials such as those mentioned immediately above are especiallyuseful as a sorption material for oily materials in pharmaceuticals,cosmetics and/or foodstuff. In a specific embodiment, the material isused as a sorption material for oily materials in pharmaceuticals. Thematerial that has the ability to function as a sorption material foroily materials is also denoted “oil sorption material”.

Furthermore, in the present context the term “sorption” is used todenote “absorption” as well as “adsorption”. It should be understoodthat whenever one of the terms is used it is intended to cover thephenomenon absorption as well as adsorption. The terms “sorptionmaterial” and “oil sorption material” is intended to have the samemeaning.

A sorption material suitable for use according to the present inventionis a solid pharmaceutically acceptable material, which—when tested asdescribed herein—

i) has an oil threshold value of 10% or more, when tested according tothe Threshold Test disclosed herein, and which material is used in acomposition of the invention further fulfilling one or both of i) andii):

i) the composition releases at least 30% of the hydrophobic or ahydrophilic or water-miscible vehicle, when tested according to theRelease Test;

ii) the composition, in the form of a tablet, contains at least about90% w/w of the oil-sorption material, and exhibits a disintegration timeof at the most 60 minutes when tested according to the Ph. Eur.Disintegration Test.

The material is especially useful as a sorption material for oilymaterials in pharmaceuticals, cosmetics and/or foodstuff, especially inpharmaceuticals.

It is important that the oil sorption material fulfills at least twotests. One of the tests is mandatory, i.e. the Threshold Test must bemet. This test gives a measure for how much oily material the oilsorption material is able to absorb while retaining suitable flowabilityproperties. It is important that an oil sorption material for useaccording to the invention (with or without oil absorbed) has a suitableflowability so that it easily can be admixed with other excipientsand/or further processed into compositions without significant problemsrelating to e.g. adherence to the apparatus involved. The test isdescribed below in Materials and Methods and guidance is given for howthe test is carried out. The Threshold Test involves the determinationof the flowability of the solid material loaded with different amountsof oil.

From above it is seen that the oil threshold value normally must exceed10% and often the oil sorption material has an oil threshold value of atleast about 15%, such as, e.g., at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, or at leastabout 45%.

An especially suitable material for use according to the invention,Aeropearl 300, has a very high oil threshold value of about 60%.Accordingly, materials that have an oil threshold value of at leastabout 50%, such as, e.g., at least about 55% or at least about 60% areused in specific embodiments of the present invention.

Furthermore, an oil sorption material for use according to the inventionmust fulfill at least one further test, namely a release test and/or adisintegration test.

The release test gives a measure of the ability of an oil sorptionmaterial to release the oil that is absorbed to the material whencontacted with water. This ability is very important especially in thosesituations where an active substance is contained in the oily material.If the oil sorption material is not capable of releasing the oil fromthe material then there is a major risk that the active substance willonly to a minor degree be released from the material. Accordingly, it isenvisaged that bioavailability problems relating to e.g. poor absorptionetc. will occur in such situations.

The requirements for the release test are that the solid pharmaceuticalacceptable material, when tested as described herein, releases at leastabout 30% such as, e.g., at least about 35%, at least about 40%, atleast about 45%, at least about 50%, at least about 55% or at leastabout 60% of an oil. As it appears from the examples herein a suitableoil sorption material like Aeroperl 300 has a much higher release.Therefore, in a specific embodiment of the invention, the solidpharmaceutical acceptable material, when tested as described herein,releases at least about 65% such as, e.g., at least about 70%, at leastabout 75% or at least about 80% of an oil.

The disintegration test is not performed on the solid material inparticulate form but on a tablet made of the solid material. Arequirement with respect to disintegration is important in order toensure that the solid material, when included in solid dosage forms,does not impart unwanted properties to the dosage form e.g. leading tounwanted properties with respect to dissolution and bioavailability ofthe active substance contained in the dosage form. For some of thematerials suitable for use according to the invention it is possible topress tablets containing 100% w/w of the solid material itself. If thisis the case, the test is carried out on such tablets. However, it isenvisaged that there may be situations where it is rather difficult toprepare tablets from the solid material alone. In such cases it ispossible to add pharmaceutically acceptable excipients normally used inthe preparation of compressed tablets up to a concentration of 10% w/wor less. Examples of suitable pharmaceutically acceptable excipientsinclude fillers, diluents, binders and lubricants. However, excipients,normally classified as disintegrants, should be avoided.

Accordingly, the solid pharmaceutical acceptable material for useaccording to invention, when tested as described herein, in the form ofa tablet should have a disintegration time of at the most 1 hour, whentested according to Ph. Eur. Disintegration test, the tablet containingabout 90% w/w or more, such as, e.g., about 92.5% w/w or more, about 95%w/w or more, about 97.5% w/w or more or about 100% of thepharmaceutically acceptable material.

In a further embodiment, the solid pharmaceutical acceptable material,when tested as described herein, in the form of a tablet has adisintegration time of at the most about 50 min, such as, e.g., at themost about 40 min, at the most about 30 min, at the most about 20 min,at the most about 10 min or at the most about 5 min, when testedaccording to Ph. Eur. Disintegration test, the tablet containing about90% w/w or more, such as, e.g., about 92.5% w/w or more, about 95% w/wor more, about 97.5% w/w or more or about 100% of the pharmaceuticallyacceptable material.

In a specific embodiment, the solid material used as a sorption materialfulfils all three tests. Thus, the solid pharmaceutical acceptablematerial, when tested as described herein,

i) has an oil threshold value of at least about 10%, such as, e.g., atleast about 15%, at least about 20%, at least about 25%, at least about30%, at least about 35%, at least about 40%, at least about 45%, atleast about 50%, at least about 55% or at least about 60%,ii) releases at least about 30% such as, e.g., at least about 35%, atleast about 40%, at least about 45%, at least about 50%, at least about55%, at least about 60%, at least about 65%, at least about 70%, atleast about 75% or at least about 80% of an oil, andiii) in the form of a tablet has a disintegration time of at the most 1hour such as at the most about 50 min, at the most about 40 min, at themost about 30 min, at the most about 20 min, at the most about 10 min orat the most about 5 min, when tested according to Ph. Eur.Disintegration test, the tablet containing about 90% w/w or more, suchas, e.g., about 92.5% w/w or more, about 95% w/w or more, about 97.5%w/w or more or about 100% of the pharmaceutically acceptable material.

Other specific embodiments of the invention are those, wherein

the solid pharmaceutical material used as a sorption material in acomposition according of the invention, when tested as described herein,

i) has an oil threshold value of at least about 55%;

the solid pharmaceutical material, when tested as described herein,

ii) releases at least about 75% of an oil; and/or

the solid pharmaceutical material, when tested as described herein,

iii) in the form of a tablet has disintegration time of at the mostabout 10 min, when tested according to Ph. Eur. Disintegration test, thetablet containing about 97.5% w/w of the pharmaceutically acceptablematerial.

The solid pharmaceutically acceptable material used as a sorptionmaterial in a composition according to the invention is normally aparticulate material in the form of e.g. powders, particles, granules,granulates etc.

Such particulate material suitable for use as an oil sorption materialhas normally a bulk density of about 0.15 g/cm³ or more such as, e.g.,at least about 0.20 g/cm³ or at least about 0.25 g/cm³.

Furthermore, the oil sorption material normally has an oil absorptionvalue of at least about 100 g oil/100 g such as, e.g., at least about150 g oil/100 g, at least about 200 g oil/100 g, at least about 250 goil/100 g, at least about 300 g oil/100 g or at least about 400 goil/100 g pharmaceutically acceptable material. The oil absorption valueis determined as described in the experimental section herein.

The present inventors have found that a common feature of some of thematerials suitable for use as oil sorption material is that they have arelatively large surface area. Accordingly, pharmaceutically acceptablematerial for use as an oil sorption material according to the inventionmay have a BET surface area of at least 5 m²/g such as, e.g., at leastabout 25 m²/g, at least about 50 m²/g, at least about 100 m²/g, at leastabout 150 m²/g, at least about 200 m²/g, at least about 250 m²/g or atleast about 275 m²/g.

As mentioned above one of the characteristic features of apharmaceutically acceptable material for use as an oil sorption materialaccording to the invention is that it retains a good flowability even ifit has been loaded with oily material. Thus, the flowability of thepharmaceutically acceptable material loaded with 25% w/w or more suchas, e.g. 30% w/w or more, 40% wow or more, 45% w/w or more, 50% w/w ormore, 55% w/w or more, 60% w/w or more, 65% w/w or more or about 70% w/wviscoleo will normally meet the Ph. Eur. requirements.

Notably, the oil sorption material may comprise a silica acid or aderivative or salt thereof such as, e.g., silicon dioxide or a polymerthereof as a pharmaceutically acceptable excipient. However, dependenton the quality employed a silicon dioxide may be a lubricant or it maybe an oil sorption material. Qualities fulfilling the latter functionseem to be most important.

In a specific embodiment, a composition or solid dosage form accordingto invention comprises a pharmaceutically acceptable excipient that is asilicon dioxide product that has properties corresponding to Aeroperl®300

Use of an oil sorption material in compositions or dosage formsaccording to the invention is very advantageous for the preparation ofpharmaceutical, cosmetic, nutritional and/or food compositions, whereinthe composition comprises oily material. One of the advantages is thatis it possible to incorporate a relatively large amount of and oilymaterial and still have a material that is solid. Thus, it is possibleto prepare solid compositions with a relatively high load of oilymaterials by use of an oil sorption material according to the invention.Within the pharmaceutical field it is an advantage to be able toincorporate a relatively large amount of an oily material in a solidcomposition especially in those situation where the active substancedoes not have suitable properties with respect to water solubility (e.g.poor water solubility), stability in aqueous medium (i.e. degradationoccurs in aqueous medium), oral bioavailability (e.g. lowbioavailability) etc., or in those situations where it is desired tomodify the release of an active substance from a composition in order toobtain a controlled, delayed, sustained and/or pulsed delivery of theactive substance. Thus, in a specific embodiment it is used in thepreparation of pharmaceutical compositions.

The oil sorption material for use in the processing into solidcompositions normally absorbs about 5% w/w or more, such as, e.g., about10% w/w or more, about 15% w/w or more, about 20% w/w or more, about 25%w/w or more, about 30% w/w or more, about 35% w/w or more, about 40% w/wor more, about 45% w/w or more, about 50 w/w or more, about 55% w/w ormore, about 60% w/w or more, about 65% w/w or more, about 70% w/w ormore, about 75% w/w or more, about 80% w/w or more, about 85% w/w ormore, about 90% w/w or more or about 95% wow or more of an oil or anoily material and is still a solid material.

Oily Materials

An important aspect of the invention is compositions or solid dosageforms comprising an oily material.

In the present context the term “oily materials” is used in a very broadsense including oils, waxes, semi-solid materials and materials thatnormally are used as solvents (such as organic solvents) or cosolventswithin the pharmaceutical industry, and the term also includestherapeutically and/or prophylactically active substances that are inliquid form at ambient temperature; furthermore the term includesemulsions like e.g. microemulsions and nanoemulsions and suspensions.The oils and oily-like materials that can be absorbed will normally beliquid at ambient or elevated temperature (for practical reasons themax. temperature is about 250° C.). They may be hydrophilic, lipophilic,hydrophobic and/or amphiphilic materials.

The oily materials that are suitable for use in the present context aresubstances or materials, which have a melting point of at least about10° C. and at the most about 250° C.

In specific embodiments of the invention, the oily material has amelting point of about 5° C. or more such as, e.g., about 10° C. ormore, about 15° C. or more, about 20° C. or more or about 25° C. ormore.

In further embodiments of the invention, the oily material has a meltingpoint of at least about 25° C. such as, e.g., at least about 30° C. atleast about 35° C. or at least about 40° C. For practical reasons, themelting point may normally not be too high, thus, the oily materialnormally has a melting point of at the most about 300° C. such as, e.g.,at the most about 250° C., at the most about 200° C., at the most about150° C. or at the most about 100° C. If the melting point is higher arelatively high temperature may promote e.g. oxidation or other kind ofdegradation of an active substance in those cases where e.g. atherapeutically and/or prophylactically active substance is included.

In the present context, melting points are determined by DSC(Differential Scanning Calorimetry). The melting point is determined asthe temperature at which the linear increase of the DSC curve intersectsthe temperature axis (see FIG. 1 for further details).

Interesting oily materials are in general substances, which are used inthe manufacture of pharmaceuticals as so-called melt binders or solidsolvents (in the form of solid dosage form), or as co-solvents oringredients in pharmaceuticals for topical use. It may be hydrophilic,hydrophobic and/or have surface-active properties. In generalhydrophilic and/or hydrophobic oily materials are suitable for use inthe manufacture of a pharmaceutical composition comprising atherapeutically and/or prophylactically active substance that has arelatively low aqueous solubility and/or when the release of the activesubstance from the pharmaceutical composition is designed to beimmediate or non-modified. Hydrophobic oily materials, on the otherhand, are normally used in the manufacture of a modified releasepharmaceutical composition. The above-given considerations aresimplified to illustrate general principles, but there are many caseswhere other combinations of oily materials and other purposes arerelevant and, therefore, the examples above should not in any way limitthe invention.

Typically, a suitable hydrophilic oily material is selected from thegroup consisting of: polyether glycols such as, e.g., polyethyleneglycols, polypropylene glycols; polyoxyethylenes; polyoxypropylenes;poloxamers and mixtures thereof, or it may be selected from the groupconsisting of: xylitol, sorbitol, potassium sodium tartrate, sucrosetribehenate, glucose, rhamnose, lactitol, behenic acid, hydroquinonmonomethyl ether, sodium acetate, ethyl fumarate, myristic acid, citricacid, Gelucire 50/13, other Gelucire types such as, e.g., Gelucire 44/14etc., Gelucire 50/10, Gelucire 62/05, Sucro-ester 7, Sucro-ester 11,Sucro-ester 15; maltose, mannitol and mixtures thereof.

A suitable hydrophobic oily material may be selected from the groupconsisting of: straight chain saturated hydrocarbons, sorbitan esters,paraffins; fats and oils such as e.g., cacao butter, beef tallow, lard,polyether glycol esters; higher fatty acid such as, e.g. stearic acid,myristic acid, palmitic acid, higher alcohols such as, e.g., cetanol,stearyl alcohol, low melting point waxes such as, e.g., glycerylmonostearate, glyceryl monooleate, hydrogenated tallow, myristylalcohol, stearyl alcohol, substituted and/or unsubstitutedmonoglycerides, substituted and/or unsubstituted diglycerides,substituted and/or unsubstituted triglycerides, yellow beeswax, whitebeeswax, carnauba wax, castor wax, japan wax, acetylate monoglycerides;NVP polymers, PVP polymers, acrylic polymers, or a mixture thereof.

In an interesting embodiment, the oily material is a polyethylene glycolhaving an average molecular weight in a range of from about 400 to about35,000 such as, e.g., from about 800 to about 35,000, from about 1,000to about 35,000 such as, e.g., polyethylene glycol 1,000, polyethyleneglycol 2,000, polyethylene glycol 3,000, polyethylene glycol 4,000,polyethylene glycol 5,000, polyethylene glycol 6000, polyethylene glycol7,000, polyethylene glycol 8,000, polyethylene glycol 9,000 polyethyleneglycol 10,000, polyethylene glycol 15,000, polyethylene glycol 20,000,or polyethylene glycol 35,000. In certain situations polyethylene glycolmay be employed with a molecular weight from about 35,000 to about100,000.

In another interesting embodiment, the oily material is polyethyleneoxide having a molecular weight of from about 2,000 to about 7,000,000such as, e.g. from about 2,000 to about 100,000, from about 5,000 toabout 75,000, from about 10,000 to about 60,000, from about 15,000 toabout 50,000, from about 20,000 to about 40,000, from about 100,000 toabout 7,000,000 such as, e.g., from about 100,000 to about 1,000,000,from about 100,000 to about 600,000, from about 100,000 to about 400,000or from about 100,000 to about 300,000.

In another embodiment, the oily material is a poloxamer such as, e.g.Poloxamer 188, Poloxamer 237, Poloxamer 338 or Poloxamer 407 or otherblock copolymers of ethylene oxide and propylene oxide such as thePluronic® and/or Tetronic® series. Suitable block copolymers of thePluronic® series include polymers having a molecular weight of about3,000 or more such as, e.g. from about 4,000 to about 20,000 and/or aviscosity (Brookfield) from about 200 to about 4,000 cps such as, e.g.,from about 250 to about 3,000 cps. Suitable examples include Pluronic®F38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105,F108, P123, F123, F127, 10R8, 17R8, 25R5, 25R8 etc. Suitable blockcopolymers of the Tetronic® series include polymers having a molecularweight of about 8,000 or more such as, e.g., from about 9,000 to about35,000 and/or a viscosity (Brookfield) of from about 500 to about 45,000cps such as, e.g., from about 600 to about 40,000. The viscosities givenabove are determined at 60° C. for substances that are pastes at roomtemperature and at 77° C. for substances that are solids at roomtemperature.

The oily material may also be a sorbitan ester such as, e.g., sorbitandiisostearate, sorbitan dioleate, sorbitan monolaurate, sorbitanmonoisostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan sesqui-isostearate, sorbitan sesquioleate,sorbitan sesquistearate, sorbitan tri-isostearate, sorbitan trioleate,sorbitan tristearate or mixtures thereof.

The oily material may of course comprise a mixture of different oilymaterials such as, e.g., a mixture of hydrophilic and/or hydrophobicmaterials.

Other suitable oily materials may be solvents or semi-solid excipientslike, e.g. propylene glycol, polyglycolised glycerides includingGelucire 44/14, complex fatty materials of plant origin includingtheobroma oil, carnauba wax, vegetable oils like e.g. almond oil,coconut oil, corn oil, cottonseed oil, sesame oil, soya oil, olive oil,castor oil, palm kernels oil, peanut oil, rape oil, grape seed oil etc.,hydrogenated vegetable oils such as, e.g. hydrogenated peanut oil,hydrogenated palm kernels oil, hydrogenated cottonseed oil, hydrogenatedsoya oil, hydrogenated castor oil, hydrogenated coconut oil; naturalfatty materials of animal origin including beeswax, lanolin, fattyalcohols including cetyl, stearyl, lauric, myristic, palmitic, stearicfatty alcohols; esters including glycerol stearate, glycol stearate,ethyl oleate, isopropyl myristate; liquid interesterified semi-syntheticglycerides including Miglycol 810/812; amide or fatty acid alcolamidesincluding stearamide ethanol, diethanolamide of fatty coconut acids,acetic acid esters of mono and diglycerides, citric acid esters of monoand diglycerides, lactic acid esters of mono and diglycerides, mono anddi-glycerides, poly-glycerol esters of fatty acids, poly-glycerolpoly-ricinoleate, propylene glycol esters of fatty acids, sorbitanmonostearates, sorbitan tristearates, sodium stearoyl lactylates,calcium stearoyl lactylates, diacetyl tartaric acid esters of mono anddiglycerides etc.

The pharmaceutical composition or a solid dosage form according to theinvention may have a concentration of the oily material in thecomposition or the dosage form of about 5% w/w or more such as, e.g.,about 10% w/w or more, about 15% w/w or more, about 20% w/w or more,about 25% w/w or more, about 30% w/w or more, about 35% w/w or more,about 40% w/w or more, about 45% w/w or more, about 50 w/w or more,about 55% w/w or more, about 60% w/w or more, about 65% w/w or more,about 70% w/w or more, about 75% w/w or more, about 80% w/w or more,about 85% w/w or more, about 90% w/w or more or about 95% w/w or more.

In specific embodiments the concentration of the oily material in acomposition or solid dosage form of the invention is in a range fromabout 20% to about 80% w/w such as, e.g., from about 25% to about 75%w/w.

One of the advantages is that is it possible to incorporate a relativelylarge amount of oily material and still have a solid material. Thus, itis possible to prepare solid compositions with a relatively high load ofoily materials by use of an oil sorption material according to theinvention. Within the pharmaceutical field it is an advantage to be ableto incorporate a relatively large amount of an oily material in a solidcomposition especially in those situation where the active substancedoes not have suitable properties with respect to water solubility (e.g.poor water solubility), stability in aqueous medium (i.e. degradationoccurs in aqueous medium), oral bioavailability (e.g. lowbioavailability) etc., or in those situations where it is desired tomodify the release of an active substance from a composition in order toobtain a controlled, delayed, sustained and/or pulsed delivery of theactive substance.

A further advantage is that the particulate material obtained is afree-flowing powder and therefore readily processable into e.g. soliddosage forms such as tablets, capsules or sachets. Normally, theparticulate material has properties that are suitable in order tomanufacture tablets by direct compression without addition of largeamounts of further additives. A suitable test for test the flowabilityof the particulate material is the method described in Ph. Eur. andmeasuring the flow rate of the material out of a funnel with a nozzle(orifice) diameter of 10.0 mm.

In an embodiment of the invention, at least a part of the fibrate may bepresent in the composition in the form of a solid dispersion including amolecular dispersion and a solid solution. Normally, 10% or more suchas, e.g., 20% or more, 30% or more, 40% or more, 50% or more, 60% ormore, 70% or more, 80% or more, 90% or more such as, e.g., 95% or moreor about 100% w/w of the active substance thereof is present in thecomposition in dissolved form.

Solid Dosage Forms

The pharmaceutical composition according to the invention is inparticulate form and may be employed as such. However, in many cases itis more convenient to present the composition in the form of granules,pellets, microspheres, nanoparticles and the like or in the form ofsolid dosage forms including tablets, tablets, beads, capsules, grains,pills, granulates, granules, powder, pellets, sachets, lozenges, trochesand the like.

A solid dosage form according to the invention may be a single unitdosage form or it may in the form of a polydepot dosage form contain amultiplicity of individual units such as, e.g., pellets, beads and/orgranules.

Usually, a pharmaceutical composition or a solid dosage form of theinvention is intended for administration via the oral, buccal orsublingual administration route.

The invention also relates to the above-mentioned presentation form.Within the scope of the invention are compositions/solid dosage formsthat are intended to release the active substance in a fast release, adelayed release or modified release manner.

A solid dosage form according to the present invention comprises apharmaceutical composition in particulate form as described above. Thedetails and particulars disclosed under this main aspect of theinvention apply mutatis mutandis to the other aspects of the invention.Accordingly, the properties with respect to increase in bioavailability,changes in bioavailability parameters, reduction in adverse food effectas well as release of one or more fibrates etc. described and/or claimedherein for pharmaceutical compositions in particulate form are analoguesfor a solid dosage form according to the present invention.

Usually, the concentration of the pharmaceutical composition inparticulate form is in a range of from about 5 to 100% w/w such as,e.g., from about 10% to about 90% w/w, from about 15% to about 85% w/w,from about 20% to about 80% w/w, from about 25% to about 80% w/w, fromabout 30% to about 80% w/w, from about 35% to about 80% w/w, from about40% to about 75% w/w, from about 45% to about 75% w/w or from about 50%to about 70% w/w of the dosage form. In an embodiment of the invention,the concentration of the pharmaceutical composition in particulate formis 50% w/w or more of the dosage form.

The solid dosage forms of the invention are very stable. For example,the fibrate is present in an amount of at least 90%, or at least 95%, orat least 100%, relative to the amount prior to storage, when assayedafter 3 months of storage at a temperature of about 40° C. and arelative humidity of about 75%. Also, the physical stability is veryhigh as can be seen from the Examples below.

The solid dosage form according to the invention is obtained byprocessing the particulate material according to the invention by meansof techniques well-known to a person skilled in the art. Usually, thisinvolves further addition of one or more of the pharmaceuticallyacceptable excipients mentioned herein.

The composition or solid dosage form according to the invention may bedesigned to release one or more fibrates in any suitable manner providedthat the increase in bioavailability is maintained. Thus, the activesubstance may be released relatively fast in order to obtain an enhancedon-set of action, it may be released so as to follow zero or first orderkinetics or it may be released in a controlled or modified manner inorder to obtain a predetermined pattern of release. Plain formulationsare also within the scope of the present invention.

The composition or solid dosage form according to the invention may alsobe coated with a film coating, an enteric coating, a modified releasecoating, a protective coating, an anti-adhesive coating etc.

A solid dosage form according to the invention may also be coated inorder to obtain suitable properties e.g. with respect to release of theactive substance. The coating may be applied on single unit dosage forms(e.g. tablets, capsules) or it may be applied on a polydepot dosage formor on its individual units.

Suitable coating materials are e.g. methylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic polymers,ethylcellulose, cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate, polyvinylalcohol,sodium carboxymethylcellulose, cellulose acetate, cellulose acetatephthalate, gelatin, methacrylic acid copolymer, polyethylene glycol,shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax,zein.

Plasticizers and other ingredients may be added in the coating material.The same or different active substance may also be added in the coatingmaterial.

The pharmaceutical composition or a solid dosage form according to theinvention is designed to release the fibrate in a suitable manner.Specific release patterns are disclosed in the appended claims to whichreference is made. Herein is also given specific relevant absorptionpatterns.

Other Embodiments of the Invention

In yet another aspect, the invention relates to a solid pharmaceuticalcomposition in particulate form comprising one or more fibrates and oneor more oily materials, the composition having a suitable flowability asdetermined according to the method described in Ph. Eur. measuring theflow rate of the composition out of a funnel with a nozzle diameter of10.0 mm. In order to avoid any adherence to the manufacturing and/orfilling equipment it is important that the particulate material isfreely flowing. This characteristic is also important in those caseswhere it is desired to process the particulate material further intoother kinds of formulations such as, e.g., solid dosage forms.

Yet another aspect of the invention relates to a solid pharmaceuticalcomposition in particulate form comprising one or more fibrates, one ormore oily materials and one or more oil-sorption materials, which

i) has an oil threshold value of 10% or more, when tested according tothe Threshold Test herein, and fulfills at least one of

ii) releases at least 30% of an oil, when tested according to theRelease Test herein, and

iii) in the form of a tablet has a disintegration time of at the most 1hour, when tested according to Ph. Eur. Disintegration test, the tabletcontaining about 90% w/w or more of the oil-sorption material. Incertain situations, it has been found that it is an advantage toincorporate a sorption material in the composition in order e.g. toenable a high concentration of an oily material. In those cases wherethe oily material has a melting point of at the most about 250° C., itmay be especially suitable to incorporate a sorption material. Suitableexamples of oily materials as well as sorption materials are givenherein.

In a further specific embodiment, the fibrate is present at least partlyin the form of a solid dispersion including a solid solution.

In a further embodiment, the present invention relates to a solidpharmaceutical composition in particulate form or a solid dosage formcomprising one or more fibrates dissolved in one or more oily materials.In this aspect, the fibrate is present in the form of a solid solutionin the particulate composition and the presence of a solid solution canbe tested by the DSC test mentioned herein. In this aspect, theparticulate composition is prepared by dissolving the fibrate in an oilymaterial optionally at elevated temperature and (optionally afteraddition of further active substances and/or one or morepharmaceutically acceptable excipients) the mixture is sprayed on acarrier as described herein. Preferably, the concentration of the oilymaterial is at least about 10% w/w.

Materials and Methods

Materials

Fenofibrate (supplied by Sigma)

Lactose monohydrate 200 mesh (from DMV)

Granulated silicium oxide, Aeroperl® 300, (Degussa)

Polyethylene glycol 6000, Pluracol® E6000 (from BASF)

Poloxamer 188, Pluronic® F-68 (from BASF)

Glyceryl monostearate, Rylo® MD50, (from Danisco Cultor), Ph. Eur.

Avicel PH200 (microcrystalline cellulose) (from FMC)

Magnesium stearate

Tablets, capsules or granules might be enteric coated with differenttypes of polymers such as hydroxypropylmethylcellulose acetate succinate(Aqoat), cellulose acetate phthalate CAP, hydroxypropylmethylcellulosephtalate HPMCP or methacrylic acid copolymers such as Eudragit L30D,Eudragit 100/S, Eudragit 100/L.Tricor Tablet Formulation

TRICOR® tablets are fenofibrate-containing tablets available for oraladministration, either containing 54 mg or 160 mg of micronizedfenofibrate per tablet.

The tablets contain the following inactive ingredients: colloidalsilicon dioxide, crospovidone, lactose monohydrate, lecithin,microcrystalline cellulose, polyvinyl alcohol, povidone, sodium laurylsulfate, sodium stearyl fumarate, talc, titanium dioxide, xanthan gum,colorant. Tricor® is indicated as a lipid regulating agent. Therecommended dosage of Tricor® is 54-160 mg/day taken with food. Tricor®tablets are provided in strengths of 54 and 160 mg, whereas Tricor®capsules are provided in strengths of 67 and 200 mg. The tablets have ahigher bioavailability than the capsules. Other trade names areLipanthyl®, Lipantil® or Catalip®.

Lipanthyl Formulation

Lipanthyl®67M results from a process in which fenofibrate isco-micronized with a solid surface-active component to give an intimateand finely divided mixture of the two ingredients.

Equipment

Laboratory scale fluid bed equipment: Strea-1.

The melt feed unit is a prototype composed of separate units for heatingof air supplies for the atomizer, pressure tank and feeding tube.Granulate was sieved manually and mixed with extragranular excipients ina Turbula mixer.

Tablet compression was performed on a single punch press, Diaf TM20.

Methods

According to the method of the invention, the fenofibrate drug wasdissolved into the melted vehicle(s) and applied on the particulatecarrier(s) as follows:

The vehicle(s) was melted in a beaker placed in a microwave oven. Thebeaker was transferred to a temperature controlled heating platesupplied with magnetic stirring. Fenofibrate was dissolved slowly in themelt at a temperature of 75° C. under magnetic stirring. The hotsolution was transferred to the pressure tank for melt spray applicationonto the carrier in the fluid bed. The granulate product was dischargedfrom the fluid bed and sieved through sieve 0.7 mm or 1.0 mm manually.The sieved product was blended with magnesium stearate for 0.5 min in aTurbula mixer. If an extragranular phase has to be incorporated, theextragranular phase was premixed with the granulate in 3 minutes in aTurbula mixer.

The tablet compression was performed on a single punch machine DiafTM20.

Threshold Test

The test involves determination of flowability according to the methoddescribed in Ph. Eur. by measuring the flow rate of the material out ofa funnel with a nozzle diameter of 10.0 mm.

Viscoleo (medium chain triglycerides MCT; Miglyol 812 N from Condea) wasadded to 100 g of the solid pharmaceutically acceptable material to betested for use according to the invention and mixed manually. Themixture obtained was sieved through sieve 0.3 mm to assure a homogenousmixture. The oil was added successively until a flow of 100 g of themixture could not flow through the nozzle. If the material to be testedhas a high bulk volume (e.g. like that of Aeroperl 300) only 50 g of themixture is used when testing these blends. The maximal concentration ofoil where flow of material could be obtained is called the ThresholdValue (given as % w/w).

Release Test

A fat-soluble colorant Sudan II (BDH Gur®) obtained from BDH VWRInternational 14.3 mg was dissolved in 50.0 g viscoleo (fractionatedmedium chain triglycerides).

10 g of the oil was added to 10.0 g of the solid pharmaceuticallyacceptable material to be tested for use according to the presentinvention and mixed until the oil was fully absorbed in the solidmaterial. The mixture was subsequently sieved through sieve 0.3 mm toachieve a homogeneous mixture.

1.00 g of the mixture was transferred to a centrifugal tube and 3.00 mlof water was added. The suspension was mixed in a blood sample turnerfor 1 hour and subsequently centrifuged for 10 minutes at 5000 rpm. Theupper phase of oil and water was transferred carefully to a beaker andthe water was evaporated in an oven at 80° C. until constant weight. Theamount of oil released from the solid material was calculated on basisof the weight of the remaining after evaporation of the water phase.

Disintegration Test

The disintegration time was determined according to the method describedin to Ph. Eur.

Dissolution Test

The test was performed in accordance with Ph. Eur 2.9.3 using the paddleapparatus. The quantification was performed using HPLC withUV-detection.

Medium: 900 ml water with 0.75% sodium lauryl sulfate (SLS) Rotationspeed: 50 rpm Temperature: 37° C. Sampling time: 10, 20, 30, 45 and 60minutes Acceptance criteria: >75% at 45 minutesDetermination of Bulk Density

The bulk density was measured by pouring 100 g of the powder in questionin a 250 ml graduated cylinder. The bulk density is given as the tappedbulk density in g/ml. The determination was performed according to Ph.Eur. (apparent volume).

Determination of Oil Absorption Value

The oil absorption value is determined by adding well-defined amounts (a10 g) of viscoleo to a well-defined amount of the pharmaceuticallyacceptable material (100 g) to be tested. The oil absorption value(expressed as g viscoleo/100 g material) is reached when a furtheraddition of 10 g oil results in a material that does not have suitableproperties with respect to flowability, i.e. the material does not meetthe meet the requirements when tested according to Ph. Eur. (flowabilitytest; see above under Threshold Test herein).

Determination of BET Surface Area

The apparatus applied was a Micrometrics Gemini 2375. The method appliedwas according to USP volumetric methods based on multiple pointdetermination.

Determination of Flowability

The flowability was determined according to the method described in Ph.Eur. measuring the flow rate of the material out of a funnel with anozzle diameter of 10.0 mm.

Determination of Weight Variation

The tablets prepared in the Examples herein were subject to a test forweight variation performed in accordance with Ph. Eur.

Determination of Average Tablet Hardness

The tablets prepared in the Examples herein were subject to at test fortablet hardness employing Schleuniger Model 6D apparatus and performedin accordance with the general instructions for the apparatus.

Determination of Solid Solution

According to the present invention, the fibrate is dissolved in avehicle. In order to substantiate this, a test involving differentialscanning calometry is performed. The test is performed on theparticulate composition, solid dosage form or mixture of vehicle andfibrate (after the solid solution is supposed to form). Standard DSCequipment connected to a PC is used.

Sample size: 10 mg in alu pans Heating rate: 5° C./min from 27° C. to110° C. Evaluation: The fibrate is considered to be in dissolved stateor non- crystalline if no fibrate endoterm peak is observed and if themelting interval does not significantly shift compared with the vehiclealone.Determination of Geometric Weight Mean Diameter d_(gw)

The geometric weight mean diameter was determined by employment of amethod of laser diffraction dispersing the particulate material obtained(or the starting material) in air. The measurements were performed at 1bar dispersive pressure in Sympatec Helos equipment, which records thedistribution of the equivalent spherical diameter. This distribution isfitted to a log normal volume-size distribution.

When used herein, “geometric weight mean diameter” means the meandiameter of the log normal volume-size distribution.

In Vivo Studies in Beagle Dogs

In vivo studies with the purpose of determining the bioavailability ofthe compositions of the present invention relative to thebioavailability of the commercially available fenofibrate tabletformulation, i.e. Tricor®, was performed using Beagle dogs.

The experimental work was performed in Denmark using four male Beagledogs each having a body weight of 12-18 kg (starting weight). Thestudies were conducted as open, non-randomised, cross-over studies. Eachanimal was its own control. Oral doses of fenofibrate was administeredaccording to the data below. The dogs were fasted overnight prior todosing (water ad libitum) and were fed 5 hours after dosing (water adlibitum). Each dog was dosed with the specified dose of fenofibratewithout taking the weight of the dog into consideration.

Blood samples were collected at vena jugularis externa at the followingpoints of time: Pre-dose, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours afterdosing. 4 ml of blood were collected, mixed with EDTA, and the sampleswere frozen (−80° C.). The blood samples were analyzed using on-lineextraction LC/MS and results were given in mg/mL. The determined fullblood concentration profiles of fenofibrate were treated using thePharmacokinetic softwear WinNonlin®, (Pharsight, California; USA) tocalculate the pharmacokinetic parameters. All data are dose adjusted,when necessary.

The following examples serve the purpose of illustration of theinvention and are not intended to limiting the scope of the presentinvention. Pharmaceutical compositions and dosage forms of the inventionare exemplified in examples 1-7. Results of in vitro dissolution testsof dosage forms of the invention are found in example 8. Results ofstability tests of dosage forms of the invention are found in example 9.Results of in vivo comparison studies in Beagle dogs (blood plasmaconcentration) are found in example 10-12.

Example 1 Immediate Release Tablet with Improved Bioavailability

Fenofibrate was dissolved at a concentration of 17% in polyethyleneglycol 6000 and Poloxamer 188 (70:30 w/w ratio) at 75° C. 244 g of themelted solution was sprayed on 200 g lactose in a fluid bed Strea-1 at75° C. The granular product was sieved through sieve 0.7 mm and blendedwith magnesium stearate for 0.5 min in a Turbula mixer. The mixture wascompressed into 10 mm tablets with a strength of 50 mg (540 mg tabletwith compound cup shaped).

Substance % mg Fenofibrate 9.30 50.00 Lactose 44.78 240.64 PEG 600031.80 170.88 Poloxamer 188 13.63 73.24 Magnesium stearate 0.50 2.69Total 100.00 537.45Mean disintegration time: 26 min, Hardness: 45 N

Example 2 Immediate Release Tablet with Improved Bioavailability

10 mm tablets of 50 mg strength (540 mg tablet with compound cup shaped)and having the following composition were prepared as described inExample 1:

Substance % mg Fenofibrate 9.30 50.00 Lactose 44.78 240.64 PEG 600045.43 244.12 Magnesium stearate 0.50 2.69 Total 100.00 537.45Mean disintegration time: 21 min, Hardness: 55 N

Example 3 Immediate Release Tablet with Improved Bioavailability

10 mm tablets of 50 mg strength (540 mg tablet with compound cup shaped)and having the following composition were prepared as described inExample 1:

Substance % mg Fenofibrate 9.30 50.00 Lactose 44.78 240.64 PEG 400031.80 170.88 Poloxamer 188 13.63 73.24 Magnesium stearate 0.50 2.69Total 100.00 537.45Mean disintegration time: 22 min, Hardness: 48 N

Example 4 Immediate Release Tablet with Improved Bioavailability

Fenofibrate was dissolved in polyethylene glycol 4000 in a concentrationof 17% at 75° C. 244 g of the melted solution was sprayed on 200 glactose in a fluid bed Strea-1 at 75° C. The granular product was sievedthrough sieve 0.7 mm and blended with magnesium stearate for 0.5 min ina Turbula mixer. The mixture was compressed into 10 mm tablets of 50 mgstrength (540 mg tablet with compound cup shaped).

Substance % mg Fenofibrate 9.30 50.00 Lactose 44.78 240.64 PEG 400045.43 244.12 Magnesium stearate 0.50 2.69 Total 100.00 537.45Mean disintegration time: 21 min, Hardness: 55 N

Example 5 Immediate Release Tablet with Improved Bioavailability

Fenofibrate was dissolved in polyethylene glycol 4000 in a concentrationof 17% at 75° C. 244 g of the melted solution was sprayed on 190 glactose in mixture with 10 g sodium lauryl sulfate (SDS) in a fluid bedStrea-1 at 75° C. The granular product was sieved through sieve 0.7 mmand blended with magnesium stearate for 0.5 min in a Turbula mixer. Themixture was compressed into 10 mm tablets of 50 mg strength (540 mgtablet with compound cup shaped).

Substance % mg Fenofibrate 9.30 50.00 Lactose 42.54 228.61 SDS 2.2312.03 PEG 4000 45.43 244.12 Magnesium stearate 0.50 2.69 Total 100.00537.45Mean disintegration time: 18 min, Hardness: 65 N

Example 6 Immediate Release Tablet with Improved Bioavailability

Fenofibrate was dissolved in a concentration of 30% in polyethyleneglycol 4000 and Poloxamer 188 (70:30 w/w ratio) at 75° C. 466 g of themelted solution was sprayed on 200 g Aeroperl 300 in a fluid bed Strea-1at 75° C. The granular product was sieved through sieve 0.7 mm andblended with magnesium stearate for 0.5 min in a Turbula mixer. Themixture was compressed into 13.5 mm tablets of 150 mg strength (720 mgtablet with compound cup shaped).

Substance % mg Fenofibrate 20.90 150.00 Aeroperl 300 29.85 214.29 PEG6000 34.13 245.00 Poloxamer 188 14.63 105.00 Mg-stearat 0.50 3.59 Total100.00 717.88Mean disintegration time: 35 min, Hardness: 35 N

Example 7 Formulations of the Invention

Tablets of 50 mg and 160 mg strength, respectively and having thefollowing compositions were prepared as described in Examples 1, 4 and6:

A B C D E Substance Ingredient mg mg mg mg mg Drug Fenofibrate 160.0950.05 50.08 50.09 159.99 Vehicle 1 PEG6000 208.12 171.09 124.29 — —PEG4000 — — — 244.57 — GMS (Rylo) — — — — 86.15 Vehicle 2 Poloxamer18889.19 73.33 53.27 — — Carrier Lactose 356.51 231.87 — 232.02 163.01Aeropearl 300 — — 63.89 — — Excipients Mg stearate 4.09 2.65 1.47 5.328.35 Avicel — — — — 417.50 Total 818.00 529.00 293.00 532.00 835.00Hardness N 60 44 44 47 102 Disintegration Minutes 25 14 30 48 >55 timeDiameter Mm Oblong 12 12 10 Oblong

Example 8 Dissolution Tests

The inventive tablet formulation A of example 7 was subjected to adissolution test as described in Methods with the following results:

Time (min) % dissolved 0 0 10 28 20 56 30 74 45 88 60 97

Example 9 Stability Tests

Samples of the inventive tablet formulation A of example 7 was storedunder the following conditions, respectively, and subjected to adissolution (stability) test as described in Methods after 1 month and 3months of storage; % dissolved is the percentage of fenofibratedissolved after 45 minutes:

% dissolved Months 25° C. and 60% RH 30° C. and 65% RH 40° C. and 75% RH0 88 — — 1 99 88 90 3 90 97 90

Samples of the inventive tablet formulation A of example 7 was storedunder the following conditions, respectively, and subjected to a fibrateassay with the following results:

mg fenofibrate Months 25° C. and 60% RH 30° C. and 65% RH 40° C. and 75%RH 0 163.8 — — 1 161.9 160.1 160.8 3 162.6 164.9 164.4

Samples of the inventive tablet formulation A of example 7 was storedunder the following conditions, respectively, and subjected to adegradation product test according to Ph. Eur. (Degradation products A,B, G and Unknown accumulated into Total Degradation Product; HPLCmethod) with the following results:

Total Degradation Product, % w/w, impurity Months 25° C. and 60% RH 30°C. and 65% RH 40° C. and 75% RH 0 0.05 — — 1 0.05 0.05 0.05 3 0.05 0.050.05

Example 10 In Vivo Study in Dogs

An in vivo study of formulation A of example 7,160 mg in Beagle dogs,performed as described above under Methods, relative to Tricor®, 160 mg(Batch no.: 098212E21), gave the following results:

Blood concentrations (mg/mL) (average of 4 dogs) after administration offormulation:

Formulation Time Invention, A (hr) Tricor ® (160 mg) (160 mg) 0 n.a.n.a. 0.5 367.5 995.8 1.0 612.5 2209.3 1.5 722.0 2627.8 2.0 725.8 2097.33.0 443.8 1219.5 4.0 295.3 930.5 6.0 160.5 642.0 8.0 250.3 869.5 12.0211.8 615.3 24.0 133.3 394.0 48.0 n.a. 164.5Relative bioavailability based on AUC (invention, A/Tricor®): 306%.Relative c_(max) (invention, A/Tricor®): 356%.

Example 11 In Vivo Study in Dogs

A second in vivo study of formulation A of example 7, 160 mg in Beagledogs, performed as described above under Methods, relative to Tricor®,160 mg (Batch no.: 098212E21), gave the following results:

Blood concentrations (mg/mL) (average of 4 dogs) after administration offormulation:

Formulation Time Invention, A (hr) Tricor ® (160 mg) (160 mg) 0 0 0 0.5339.3 3616.0 1.0 1318.8 3724.8 1.5 1313.3 2982.0 2.0 1390.0 2355.8 3.01361.3 1359.5 4.0 1019.3 1309.5 6.0 969.3 973.8 8.0 667.0 1113.0 12.0390.3 768.5 24.0 183.3 295.0 48.0 85.0 302.0Relative bioavailability based on AUC (invention, A/Tricor®): 198%.Relative c_(max) (invention, A/Tricor®): 238%.

Example 12 In Vivo Study in Dogs

An in vivo study of the formulations B, C and D of example 7, 2×50 mg inBeagle dogs, performed as described above under Methods, relative toLipanthyl®67M, 2×67 mg (Batch no.: 75641), gave the following results:

Blood concentrations (mg/mL) (average of 4 dogs) after administration offormulation:

Formulation Time Lipanthyl ® 67M Invention, B Invention, C Invention, D(hr) (2 × 67 mg) (2 × 50 mg) (2 × 50 mg) (2 × 50 mg) 0 0 0 0 0 0.5 187.32769.5 227.3 546.0 1.0 669.5 3526.8 521.5 1381.5 1.5 960.3 3106.3 858.31615.5 2.0 895.3 2938.0 989.3 1566.8 3.0 433.0 2465.5 902.5 1503.3 4.0240.0 1492.3 783.8 1719.0 6.0 77.8 809.5 655.8 1034.5 8.0 79.3 1202.8409.0 1056.0 12.0 291.3 848.0 269.8 597.3 24.0 82.5 378.0 163.8 282.848.0 19.3 18.8 51.5 36.5 72.0 0 0 0 0Relative bioavailability based on AUC (invention, B/Lipanthyl®67M):532%.Relative c_(max)(invention, BA/Lipanthyl®67M): 548%.Relative bioavailability based on AUC (invention, C/Lipanthyl®67M):228%.Relative c_(max)(invention, C/Lipanthyl®67M): 161%.Relative bioavailability based on AUC (invention, D/Lipanthyl®67M):424%.Relative c_(max)(invention, D/Lipanthyl®67M): 329%.

1. A tablet comprising fenofibrate in a vehicle, wherein (i) the vehiclecomprises polyethylene glycol having an average molecular weight of 3000daltons to 35000 daltons and a poloxamer in a weight proportion ofbetween 1:3 and 10:1, and (ii) the tablet comprises 10 to 35% by weightof fenofibrate, based upon 100% total weight of the tablet.
 2. Thetablet according to claim 1, wherein the vehicle further comprises awater-miscible polar lipid, higher alcohol, glyceryl monooleate,substituted and/or unsubstituted monoglyceride, substituted and/orunsubstituted diglyceride, or a mixture thereof.
 3. The tablet accordingto claim 1, wherein the vehicle further comprises polyoxyethyleneoxides, polyoxyethylene stearates, poly-epsiloncaprolactone or anymixture thereof.
 4. The tablet according to claim 1, wherein thepoloxamer is poloxamer
 188. 5. The tablet according to claim 1, whereinthe polyethylene glycol has an average molecular weight of about 6000daltons.
 6. The tablet according to claim 1, wherein the vehicle isnon-aqueous.
 7. The tablet according to claim 1, wherein theconcentration of fenofibrate in the vehicle is in the range of 10% w/wto 90% w/w, based on the total weight of the fenofibrate and thevehicle.
 8. The tablet according to claim 1, wherein the concentrationof fenofibrate in the vehicle is in the range of 15% w/w to 90% w/w,based on the total weight of the fenofibrate and the vehicle.
 9. Thetablet according to claim 1, wherein the concentration of fenofibrate inthe vehicle is in the range of 15% w/w to 80% w/w, based on the totalweight of the fenofibrate and the vehicle.
 10. The tablet according toclaim 1, wherein the concentration of fenofibrate in the vehicle is inthe range of 20% to 75% w/w, based on the total weight of thefenofibrate and the vehicle.
 11. The tablet according to claim 1,wherein at least 75% of the fenofibrate is released within about 45minutes when tested in an in vitro dissolution test according to Ph.Eur. dissolution test (paddle) employing water with 0.75% sodium laurylsulfate as dissolution medium, 50 rpm and a temperature of about 37° C.12. The tablet according to claim 11, wherein the dosage form, after 3months of storage at a temperature of about 40° C. and a relativehumidity of about 75%, releases at least 75% of the fenofibrate withinabout 45 minutes when tested in an in vitro dissolution test accordingto Ph. Eur. dissolution test (paddle) employing water with 0.75% sodiumlauryl sulfate as dissolution medium, 50 rpm and a temperature of about37° C.
 13. The tablet according to claim 1 which further comprises oneor more pharmaceutically acceptable excipients.
 14. The tablet accordingto claim 13, wherein the pharmaceutical acceptable excipients areselected from the group consisting of fillers, diluents, disintegrants,binders, glidants and lubricants.
 15. The tablet according to claim 13,wherein at least one pharmaceutical acceptable excipient is a silicaacid or a derivative or salt thereof.
 16. The tablet according to claim13, wherein at least one pharmaceutical acceptable excipient is a silicaacid or a derivative or salt thereof selected from the group consistingof silicates, silicon dioxide; magnesium aluminosilicate, magnesiumaluminometasilicate, bentonite, kaolin, magnesium trisilicate,montmorillonite and/or saponite.
 17. The tablet according to claim 13,wherein at least one pharmaceutical acceptable excipient is selectedfrom silicon dioxide, magnesium aluminosilicate, and magnesiumaluminometasilicate.
 18. The tablet according to claim 1, which furthercomprises a pharmaceutical acceptable additive selected from the groupconsisting of flavoring agents, coloring agents, taste-masking agents,pH-adjusting agents, buffering agents, preservatives, stabilizingagents, anti-oxidants, wetting agents, humidity-adjusting agents,surface-active agents, suspending agents and absorption enhancingagents.
 19. The tablet according to claim 1, which is a unit dosageform.
 20. The tablet according to claim 1, wherein the individual unitsof the solid dosage form are coated with a coating selected from thegroup consisting of film coatings, modified release coatings, entericcoatings, protective coatings and anti-adhesive coatings.
 21. The tabletaccording to claim 1, wherein the fenofibrate is embedded in a matrixthat releases the fenofibrate by diffusion.
 22. The tablet according toclaim 21, wherein the matrix remains substantially intact during theperiod of drug release.
 23. The tablet according to claim 1, wherein thefenofibrate is embedded in a matrix that releases the fenofibrate byeroding.
 24. The tablet according to claim 1, wherein the fenofibrate isreleased from the dosage form by diffusion through a substantiallywater-insoluble coating.
 25. The tablet according to claim 1, whereinthe fenofibrate is stable.
 26. The tablet according to claim 25, whereinthe fenofibrate is present in an amount of at least 90%, relative to theamount prior to storage, when assayed after 3 months of storage at atemperature of about 40° C. and a relative humidity of about 75%.
 27. Amethod of manufacturing the tablet of claim 1 comprising the steps of:i) Bringing the vehicle in liquid form, if applicable, ii) Maintainingthe liquid vehicle at a temperature below the melting point of thefenofibrate, iii) Dissolving the desired amount of fenofibrate in thevehicle, iv) Spraying the resulting solution onto a solid carrier havinga temperature below the melting point of the vehicle, v) Mechanicallyworking the resulting composition to obtain particles, and vi)Optionally subjecting the particulate material to conventional methodsfor preparing tablets.
 28. A tablet comprising fenofibrate in a vehicle,wherein (i) the vehicle comprises polyethylene glycol having an averagemolecular weight of 3000 daltons to 35000 daltons and a poloxamer in aweight proportion of between 1:3 and 10:1, and (ii) the tablet comprises10 to 35% by weight of fenofibrate, based upon 100% total weight of thetablet, and wherein the tablet is prepared by (a) forming a mixturecomprising poloxamer and polyethylene glycol having an average molecularweight of 3000 daltons to 35000 daltons in which fenofibrate isdissolved (b) spraying the mixture formed in step (a) onto a solidcarrier, and (c) forming a tablet from the product of step (b).
 29. Thetablet of claim 1, wherein i) the vehicle comprises a mixture ofpoloxamer 188 and polyethylene glycol having an average molecular weightof about 6000 daltons, and ii) at least 75% of the fenofibrate isreleased from the tablet within about 45 minutes when tested in an invitro dissolution test according to Ph. Eur. dissolution test (paddle)employing water with 0.75% sodium lauryl sulfate as dissolution medium,50 rpm and a temperature of about 37° C.
 30. A tablet comprisingfenofibrate in a vehicle, wherein (i) the vehicle comprises polyethyleneglycol having an average molecular weight of 3000 daltons to 35000daltons and a poloxamer in a weight proportion of between 2:1 and 3:1,and (ii) the tablet comprises at least 25% by weight of fenofibrate,based upon the total weight of fenofibrate and vehicle in the tablet.31. A tablet comprising fenofibrate in a vehicle, wherein (i) thevehicle comprises polyethylene glycol having an average molecular weightof 3000 daltons to 35000 daltons and a poloxamer in a weight proportionof between 2:1 and 3:1, and (ii) the tablet comprises at least 25% byweight of fenofibrate, based upon the total weight of fenofibrate andvehicle in the tablet, and wherein the tablet is prepared by (a) forminga mixture comprising poloxamer and polyethylene glycol having an averagemolecular weight of 3000 daltons to 35000 daltons in which fenofibrateis dissolved, (b) spraying the mixture formed in step (a) onto a solidcarrier, and (c) forming a tablet from the product of step (b).
 32. Thetablet of claim 30, wherein the tablet comprises at least 30% by weightof fenofibrate, based upon the total weight of fenofibrate and vehiclein the tablet.
 33. The tablet of claim 31, wherein the tablet comprisesat least 30% by weight of fenofibrate, based upon the total weight offenofibrate and vehicle in the tablet.
 34. A tablet comprisingcrystalline fenofibrate in a vehicle, wherein (i) the vehicle comprisespolyethylene glycol having an average molecular weight of 3000 daltonsto 35000 daltons and a poloxamer in a weight proportion of between 1:3and 10:1, and (ii) the tablet comprises 10 to 35% by weight offenofibrate, based upon 100% total weight of the tablet.
 35. A tabletcomprising crystalline fenofibrate in a vehicle, wherein (i) the vehiclecomprises polyethylene glycol having an average molecular weight of 3000daltons to 35000 daltons and a poloxamer in a weight proportion ofbetween 2:1 and 3:1, and (ii) the tablet comprises at least 25% byweight of fenofibrate, based upon the total weight of fenofibrate andvehicle in the tablet.
 36. The tablet of claim 1, wherein the tabletfurther comprises a solid earner.
 37. The tablet of claim 30, whereinthe tablet further comprises a solid carrier.
 38. The tablet of claim34, wherein the tablet further comprises a solid carrier.
 39. The tabletof claim 35, wherein the tablet further comprises a solid carrier. 40.The tablet of claim 36, wherein the solid carrier is lactose.
 41. Thetablet of claim 37, wherein the solid carrier is lactose.
 42. The tabletof claim 38, wherein the solid carrier is lactose.
 43. The tablet ofclaim 39, wherein the solid carrier is lactose.